Nucleoside drugs have been used clinically for decades for the treatment of viral infections and proliferative disorders such as cancer. Most nucleoside drugs (analogues) are classified as antimetabolites. After they enter cells, nucleoside analogues are phosphorylated successively to nucleotide 5′-mono-phosphates, 5′-di-phosphates, and 5′-tri-phosphates. In some cases, nucleotide tri-phosphates, e.g., 3′-azido-3′-deoxythymidine tri-phosphate (AZT, an anti-human immunodeficiency virus (HIV) drug) and arabinosylcytosine tri-phosphate (cytarabine, an anticancer drug), are the active chemical entities that inhibit DNA or RNA synthesis through competitive inhibition of polymerases and subsequent incorporation of modified nucleotides into DNA or RNA sequences. In a few cases, nucleoside analogues exert effects as their 5′-monophosphate or 5′-diphosphate. For instance, 5-fluoro-2′-deoxyuridine 5′-mono-phosphate (an anticancer drug) and 2′,2′-difluoro-2′-deoxycytidine 5′-di-phosphate (an anticancer drug) have been shown to inhibit thymidylate synthase and ribonucleotide reductase, respectively. Although unphosphorylated nucleoside analogues themselves may act as adenosine kinases inhibitors and adenosine receptor ligands, currently, clinically-useful nucleoside drugs primarily depend on cellular activation by nucleoside and nucleotide kinases.
Viral infections are a major threat to human health and account for many serious infectious diseases. The most notable viruses are the blood-borne viruses (BBV), which include hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV, which are all linked by their mode of transmission, i.e., through blood or bodily fluids.
The Flaviviridae is a group of positive single-stranded RNA viruses with a genome size from 9-15 kilobases (kb). The Flaviviridae consist of various genera including Flavivirus and Hepacivirus. Flavivirus includes Dengue, Japanese Tick-Borne, and Yellow Fever viruses. Apart from these major groups, there are some additional Flavivirus that are unclassified. Hepacivirus include only one species, the Hepatitis C virus, which is composed of many genotypes and subtypes.
Hepatitis C virus is a major cause of viral hepatitis and has infected more than 200 million people worldwide. Hepatitis C virus has a positive-strand RNA genome enclosed in a nucleocapsid and lipid envelope. The HCV genome is approximately 9.6 kb in length and encodes a polyprotein of about 3,000 amino acids (Dymock et al. Antiviral Chemistry & Chemotherapy 2000, 11, 79). Current treatment for HCV infection is restricted to immunotherapy with interferon-α alone or in combination with ribavirin, a nucleoside analogue. However, this treatment is effective in only about half the patient population. Recently, several PCT patent applications (WO 99/43691, WO 01/32153, WO 01/60315, WO 01/79246, WO 01/90121, WO 01/92282, WO 02/18404, WO 02/057287, and WO 02/057425) have described nucleoside analogues as anti-HCV agents in in vitro assays.
Hepatitis B virus has acutely infected almost a third of the human population, and about 5% of the infected are chronic carriers of the virus (Delaney W E et al., Antiviral Chemistry & Chemotherapy 2001, 12, 1-35). Chronic HBV infection causes liver damage that frequently progresses to cirrhosis and/or liver cancer later in life. Despite the availability and widespread use of effective vaccines and chemotherapy, the number of chronic HBV carriers approaches 400 million worldwide.
Human immunodeficiency virus causes progressive degeneration of the immune system, leading to the development of AIDS. A number of drugs have been used clinically to treat AIDS, including reverse transcriptase inhibitors and protease inhibitors. Currently, combination therapies are used widely for the treatment of AIDS in order to reduce drug resistance. Despite the progress in the development of anti-HIV drugs, AIDS is still one of the leading epidemic diseases.
Apart from the BBV's discussed above, certain other acute viral infections also pose a great threat to human life, including infections of Herpes Simplex virus (HSV), cytomegalovirus (CMV), influenza viruses, West Nile virus, Coronaviruses, causing for example, severe acute respiratory syndrome (SARS), Variola virus (causing smallpox), Epstein-Barr virus (EBV), Varicella zoster virus (VZV), and Human respiratory syncytial virus (RSV). Accordingly, the broad range of associated infectious diseases and the propensity for viral mutation highlight the continued need for the development of different antiviral drugs.
Bacterial infections have long been the source of many infectious diseases. The widespread use of antibiotics has produced many new strains of life-threatening antibiotic resistant bacteria. Fungal infections are another type of infectious disease, some of which are also life-threatening. There is an ever increasing demand for the treatment of bacterial and fungal infections. As such, antimicrobial drugs based on new mechanisms of action are especially important.
Proliferative disorders (for example, cancer) are some of the most life-threatening diseases today and have been investigated intensively for decades. Cancer is currently the second leading cause of death in the United States, and over 500,000 people die annually from this proliferative disorder. All of the various nucleated cell types of the body can be transformed into benign or malignant tumour cells. Transformation of normal cells into cancer cells is a complex process and is not understood fully. Cancer treatment includes primarily surgery, radiation therapy, and chemotherapy. While chemotherapy can be used to treat many types of cancer, surgery and radiation therapy are limited to certain cancers at certain sites of the body. There are a number of anticancer drugs widely used clinically. Among them are alkylating agents, such as cisplatin, and antimetabolites, such as 5-fluorouracil and gemcitabine. Although surgery, radiation therapy, and chemotherapy are available to treat cancer patients, there is no cure for cancer at the present time. Cancer research remains one of the most important focuses of medical and pharmaceutical organizations.
Numerous examples exist in the literature for the synthesis of a variety of modified nucleosides (Chemistry of Nucleosides and Nucleotides, Vol. 1 (1988), Vol. 2 (1991), Vol. 3 (1994), edited by Leroy B. Townsend, Plenum Press). However, there are certain classes of nucleoside compounds that have not been explored fully for their antiviral and anti-proliferative activities. One such class is the bicyclic nucleosides.
Similarly, cycloalkyl-substituted bicyclic nitrogenous base analogues are being employed as protein kinase inhibitors to combat uncontrolled cell growth, such as is described in U.S. Patent Application Publication No. 2007/0203143.